Pharma Fridays – December 6, 2024

An Endocrine News roundup of the week’s pharmaceutical news, breakthroughs, and general information. *

Amylyx Announces Pivotal Phase 3 GLP-1 Trial Design in Post-Bariatric Hypoglycemia

On December 4, Amylyx announced the design of its pivotal Phase 3 LUCIDITY clinical trial for avexitide, an investigational, first-in-class glucagon-like peptide-1 (GLP-1) receptor antagonist, for the treatment of post-bariatric hypoglycemia (PBH).

LUCIDITY is designed to evaluate the FDA-agreed upon primary outcome of reduction in hypoglycemia events and to have similar inclusion and exclusion criteria to the previous Phase 2 trials of avexitide in PBH. Amylyx expects that the first study participant will be dosed in the first quarter of 2025, followed by expected completion of recruitment in 2025, and anticipates topline data in 2026.

“Our goal in Phase 3 is to align the trial design as closely as possible with the prior studies. Importantly, we believe LUCIDITY is well powered to detect a treatment effect. We look forward to continuing to collaborate with study investigators and the PBH community as we seek to initiate LUCIDITY and advance avexitide through the clinical development process.” – Camille L. Bedrosian, MD, chief medical officer, Amylyx

LUCIDITY will be a multicenter, randomized, double-blind, placebo-controlled Phase 3 clinical trial evaluating the efficacy and safety of avexitide in participants with PBH following Roux-en-Y gastric bypass (RYGB) surgery. The Phase 3 trial will be conducted at approximately 20 sites in the U.S. Approximately 75 participants will be randomized 3:2 to receive either 90 mg of avexitide subcutaneously once daily or placebo. The trial will include a three-week run-in period and a 16-week double-blind treatment period. Participants who complete the double-blind period of the planned study will be eligible to enter an open-label extension (OLE) period with a duration of 32 weeks. The primary efficacy objective of LUCIDITY will evaluate the reduction in the composite of Level 2 and Level 3 hypoglycemia events through Week 16. Safety and tolerability will also be evaluated.

“PBH is believed to result from an excessive GLP-1 response leading to persistent, recurrent, and debilitating hypoglycemia events that take a profound toll on someone’s quality of life. Avexitide is designed to bind to the GLP-1 receptor and inhibit the effects of excessive GLP-1 in PBH, mitigating hypoglycemia by decreasing insulin secretion and stabilizing blood glucose levels. We are excited to evaluate avexitide, which has FDA Breakthrough Therapy and Orphan Drug Designations, in the Phase 3 LUCIDITY trial, following two Phase 2 clinical studies that demonstrated compelling clinical data supporting avexitide’s ability to significantly reduce the rates of hypoglycemia events,” said Endocrine Society member Camille L. Bedrosian, MD, chief medical officer of Amylyx. “Our goal in Phase 3 is to align the trial design as closely as possible with the prior studies. Importantly, we believe LUCIDITY is well powered to detect a treatment effect. We look forward to continuing to collaborate with study investigators and the PBH community as we seek to initiate LUCIDITY and advance avexitide through the clinical development process.”

LUCIDITY was informed by data from five clinical trials of avexitide in people with PBH showing consistent, dose-dependent effects across studies. The five clinical trials include a Phase 1 trial, a single ascending dose trial, a multiple ascending dose trial, and two Phase 2 trials:

• In the Phase 2 (PREVENT), 28-day, randomized, placebo-controlled crossover trial (N=18), results showed a significant reduction in rates of Level 2 and 3 hypoglycemia events in participants with PBH after RYGB surgery following treatment with 30 mg twice daily and 60 mg once daily of avexitide compared with placebo. PREVENT’s primary endpoint was met with statistical significance, showing both avexitide dosing regimens improved the lowest glucose level (nadir) after a meal as measured during formal mixed meal tolerance testing (MMTT). Mean plasma glucose nadir was increased by 21% (p=0.001) and 26% (p=0.0002) following avexitide 30 mg twice daily and 60 mg once daily dosing, respectively, compared to placebo.
• In the Phase 2b, 28-day, open-label, investigator-initiated, crossover trial (N=16), 90 mg once daily and 45 mg twice daily of avexitide met its primary endpoint and significantly reduced rates of hypoglycemia events in participants following RYGB surgery and other upper-gastrointestinal surgeries. Participants in the Phase 2b trial receiving 90 mg once daily of avexitide, the dose Amylyx plans to evaluate in LUCIDITY, saw a statistically significant 53% reduction in Level 2 hypoglycemia events (p=0.004) and a statistically significant 66% reduction in Level 3 hypoglycemia events (p=0.0003).

Avexitide was generally well tolerated, with a favorable safety profile replicated across the clinical trials.

Amylyx will present the trial design at the World Congress on Insulin Resistance, Diabetes & Cardiovascular Disease (WCIRDC) in Los Angeles on December 12-14, 2024. Following the conclusion of the poster presentation on December 12, the poster will be made available on the “Publications” page of the Amylyx website.

About Avexitide

Avexitide is an investigational, first-in-class glucagon-like peptide-1 (GLP-1) receptor antagonist that has been evaluated in five clinical trials for post-bariatric hypoglycemia (PBH) and has also been studied in congenital hyperinsulinism (HI). The U.S. Food and Drug Administration (FDA) has granted avexitide Breakthrough Therapy Designation for both indications, Rare Pediatric Disease Designation in congenital HI, and Orphan Drug Designation for the treatment of hyperinsulinemic hypoglycemia (which includes PBH and congenital HI). Avexitide is designed to bind to the GLP-1 receptor on pancreatic islet beta cells and inhibit the effect of GLP-1 to mitigate hypoglycemia by decreasing insulin secretion and stabilizing blood glucose levels. In PBH, excessive GLP-1 can lead to the hypersecretion of insulin and subsequent debilitating hypoglycemia events. In two Phase 2 PBH trials, avexitide demonstrated highly statistically significant reductions in hypoglycemia events. These events can lead to autonomic and neuroglycopenic symptoms that can have a devastating impact on daily living.

About Post-Bariatric Hypoglycemia (PBH)

Symptomatic post-bariatric hypoglycemia (PBH) is a condition that affects approximately 8% of people who have undergone bariatric surgery, or approximately 160,000 people, in the U.S. PBH is thought to be caused by an excessive glucagon-like peptide-1 (GLP-1) response leading to hypoglycemia and impaired quality of life. PBH can cause debilitating hypoglycemia events associated with inadequate supply of glucose to the brain, known as neuroglycopenia. Clinical manifestations can include impaired cognition, loss of consciousness, and seizures. PBH is also associated with a high degree of disability that can result in major disruptions to independent living. There are no approved therapies for PBH.

*Inclusion in Pharma Fridays does not suggest an endorsement by Endocrine News or the Endocrine Society.